A Role for the β Isoform of Protein Kinase C in Fear Conditioning

The protein kinase C family of enzymes has been implicated in synaptic plasticity and memory in a wide range of animal species, but to date little information has been available concerning specific roles for individual isoforms of this category of kinases. To investigate the role of the β isoform of PKC in mammalian learning, we characterized mice deficient in the PKCβ gene using anatomical, biochemical, physiological, and behavioral approaches. In our studies we observed that PKCβ was predominantly expressed in the neocortex, in area CA1 of the hippocampus, and in the basolateral nucleus of the amygdala. Mice deficient in PKCβ showed normal brain anatomy and normal hippocampal synaptic transmission, paired pulse facilitation, and long-term potentiation and normal sensory and motor responses. The PKCβ knock-out animals exhibited a loss of learning, however; they suffered deficits in both cued and contextual fear conditioning. The PKC expression pattern and behavioral phenotype in the PKCβ knock-out animals indicate a critical role for the β isoform of PKC in learning-related signal transduction mechanisms, potentially in the basolateral nucleus of the amygdala.

[1]  Sweatt Jd,et al.  Toward a molecular explanation for long-term potentiation. , 1999 .

[2]  J. Sweatt,et al.  The Mitogen-Activated Protein Kinase Cascade Couples PKA and PKC to cAMP Response Element Binding Protein Phosphorylation in Area CA1 of Hippocampus , 1999, The Journal of Neuroscience.

[3]  U. Müller Second messenger pathways in the honeybee brain: Immunohistochemistry of protein kinase A and protein kinase C , 1999, Microscopy research and technique.

[4]  D. Gerendasy,et al.  Substrate Phosphorylation in the Protein Kinase Cγ Knockout Mouse* , 1999, The Journal of Biological Chemistry.

[5]  A. Maelicke,et al.  Expression of protein kinase C gene family members is temporally and spatially regulated during neural development in vitro. , 1998, European journal of cell biology.

[6]  C. Stevens,et al.  Regulation of the Readily Releasable Vesicle Pool by Protein Kinase C , 1998, Neuron.

[7]  A. Beaudet,et al.  Alpha7 nicotinic receptor subunits are not necessary for hippocampal-dependent learning or sensorimotor gating: a behavioral characterization of Acra7-deficient mice. , 1998, Learning & memory.

[8]  I. Black,et al.  NMDA receptor subunits in the postsynaptic density of rat brain: expression and phosphorylation by endogenous protein kinases. , 1998, Brain research. Molecular brain research.

[9]  P. Conn,et al.  Protein Kinase C and A3 Adenosine Receptor Activation Inhibit Presynaptic Metabotropic Glutamate Receptor (mGluR) Function and Uncouple mGluRs from GTP-Binding Proteins , 1998, The Journal of Neuroscience.

[10]  F. Hobbs,et al.  Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase* , 1998, The Journal of Biological Chemistry.

[11]  D. Johnston,et al.  Downregulation of Transient K+ Channels in Dendrites of Hippocampal CA1 Pyramidal Neurons by Activation of PKA and PKC , 1998, The Journal of Neuroscience.

[12]  Stephen Maren,et al.  Overtraining Does Not Mitigate Contextual Fear Conditioning Deficits Produced by Neurotoxic Lesions of the Basolateral Amygdala , 1998, The Journal of Neuroscience.

[13]  W. Sossin,et al.  Long-term changes in excitability induced by protein kinase C activation in Aplysia sensory neurons. , 1998, Journal of neurophysiology.

[14]  M. Gallagher,et al.  Spatial memory is related to hippocampal subcellular concentrations of calcium-dependent protein kinase C isoforms in young and aged rats. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Jacqueline N. Crawley,et al.  A Proposed Test Battery and Constellations of Specific Behavioral Paradigms to Investigate the Behavioral Phenotypes of Transgenic and Knockout Mice , 1997, Hormones and Behavior.

[16]  Takashi Yamamoto,et al.  Rat gustatory memory requires protein kinase C activity in the amygdala and cortical gustatory area , 1997, Neuroreport.

[17]  E. Kandel,et al.  Genetic Demonstration of a Role for PKA in the Late Phase of LTP and in Hippocampus-Based Long-Term Memory , 1997, Cell.

[18]  J. Sweatt,et al.  Enhanced phosphorylation of the postsynaptic protein kinase C substrate RC3/neurogranin during long-term potentiation , 1997, Brain Research.

[19]  C. Chiamulera,et al.  Effects of the metabotropic glutamate receptor antagonist MCPG on spatial and context-specific learning , 1996, Neuropharmacology.

[20]  David J. Anderson,et al.  Subregion- and Cell Type–Restricted Gene Knockout in Mouse Brain , 1996, Cell.

[21]  J. Sweatt,et al.  Transient Activation of Cyclic AMP-dependent Protein Kinase during Hippocampal Long-term Potentiation* , 1996, The Journal of Biological Chemistry.

[22]  S. Tonegawa,et al.  Phorbol ester effects at hippocampal synapses act independently of the gamma isoform of PKC. , 1996, Learning & memory.

[23]  A. Tarakhovsky,et al.  Immunodeficiency in Protein Kinase Cβ-Deficient Mice , 1996, Science.

[24]  E. Yamoah,et al.  Protein Kinase and G-Protein Regulation of Ca2+Currents in Hermissenda Photoreceptors by 5-HT and GABA , 1996, The Journal of Neuroscience.

[25]  R. Huganir,et al.  Characterization of Multiple Phosphorylation Sites on the AMPA Receptor GluR1 Subunit , 1996, Neuron.

[26]  E R Kandel,et al.  Presynaptic facilitation revisited: state and time dependence , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  J. Sweatt,et al.  Autonomously active protein kinase C in the maintenance phase of N-methyl-D-aspartate receptor-independent long term potentiation. , 1994, The Journal of biological chemistry.

[28]  P Andersen,et al.  Specificity of protein kinase inhibitor peptides and induction of long-term potentiation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[29]  I. Izquierdo,et al.  Post-training intrahippocampal infusion of protein kinase C inhibitors causes amnesia in rats. , 1994, Behavioral and neural biology.

[30]  L. Dekker,et al.  Protein kinase C--a question of specificity. , 1994, Trends in biochemical sciences.

[31]  S. Tonegawa,et al.  PKCγ mutant mice exhibit mild deficits in spatial and contextual learning , 1993, Cell.

[32]  T. Sacktor,et al.  Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[33]  J. Sweatt,et al.  Nitric oxide synthase-independent long-term potentiation in area CA1 of hippocampus. , 1993, Neuroreport.

[34]  A. Routtenberg,et al.  Learning selectively increases protein kinase C substrate phosphorylation in specific regions of the chick brain. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. W. Rudy,et al.  Brief exposure to an enriched environment improves performance on the Morris water task and increases hippocampal cytosolic protein kinase C activity in young rats , 1992, Behavioural Brain Research.

[36]  K. Suzuki,et al.  A new member of the protein kinase C family, nPKC theta, predominantly expressed in skeletal muscle , 1992, Molecular and cellular biology.

[37]  J H Wang,et al.  Postsynaptic protein kinase C essential to induction and maintenance of long-term potentiation in the hippocampal CA1 region. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[38]  E. Hargreaves,et al.  Hyperactivity, hyper-reactivity, and sensorimotor deficits induced by low doses of the N-methyl-d-aspartate non-competitive channel blocker MK801 , 1992, Behavioural Brain Research.

[39]  Y. Nishizuka,et al.  Isolation and characterization of delta-subspecies of protein kinase C from rat brain. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[40]  K. Suzuki,et al.  Purification and characterization of protein kinase C epsilon from rabbit brain. , 1992, Biochemistry.

[41]  S. J. Chen,et al.  Persistent protein kinase activation in the maintenance phase of long-term potentiation. , 1991, The Journal of biological chemistry.

[42]  J. W. Rudy,et al.  Acute phorbol ester treatment improves spatial learning performance in rats , 1991, Behavioural Brain Research.

[43]  W. Quinn,et al.  Deficient protein kinase C activity in turnip, a Drosophila learning mutant. , 1991, The Journal of biological chemistry.

[44]  D. Storm,et al.  Distribution of mRNA for the calmodulin-sensitive adenylate cyclase in rat brain: Expression in areas associated with learning and memory , 1991, Neuron.

[45]  J. Farley,et al.  Protein kinase C inhibitors prevent induction and continued expression of cell memory in Hermissenda type B photoreceptors. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  K. Suzuki,et al.  A phorbol ester receptor/protein kinase, nPKC eta, a new member of the protein kinase C family predominantly expressed in lung and skin. , 1990, The Journal of biological chemistry.

[47]  R. Tsien,et al.  Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. , 1989, Science.

[48]  C. Tanaka,et al.  Immunocytochemical localization of beta II subspecies of protein kinase C in rat brain. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Y. Nishizuka,et al.  Immunocytochemical localization of the beta I subspecies of protein kinase C in rat brain. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Roberto Malinow,et al.  Persistent protein kinase activity underlying long-term potentiation , 1988, Nature.

[51]  Hiroshi Kase,et al.  Inhibitors of calmodulin and protein kinase C block different phases of hippocampal long-term potentiation , 1988, Brain Research.

[52]  Y. Nishizuka,et al.  Identification of three additional members of rat protein kinase C family: gd‐, ϵ‐ and ξ‐subspecies , 1987 .

[53]  F. Huang,et al.  Differential distribution of protein kinase C isozymes in the various regions of brain. , 1987, The Journal of biological chemistry.

[54]  A. Ullrich,et al.  Multiple, distinct forms of bovine and human protein kinase C suggest diversity in cellular signaling pathways. , 1986, Science.

[55]  A. Ullrich,et al.  The complete primary structure of protein kinase C--the major phorbol ester receptor. , 1986, Science.

[56]  Robert C. Malenka,et al.  Potentiation of synaptic transmission in the hippocampus by phorbol esters , 1986, Nature.

[57]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[58]  J. Sweatt,et al.  Toward a molecular explanation for long-term potentiation. , 1999, Learning & memory.

[59]  D. Nicholls Chapter 2 Presynaptic modulation of glutamate release , 1998 .

[60]  D. Nicholls Presynaptic modulation of glutamate release. , 1998, Progress in brain research.

[61]  T. Tully,et al.  The Drosophila mutation turnip has pleiotropic behavioral effects and does not specifically affect learning. , 1997, Learning & memory.

[62]  J. Disterhoft,et al.  γisoform‐selective changes in PKC immunoreactivity after trace eyeblink conditioning in the rabbit hippocampus , 1997, Hippocampus.

[63]  A. Tarakhovsky,et al.  Immunodeficiency in protein kinase cbeta-deficient mice. , 1996, Science.

[64]  J J Kim,et al.  PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning. , 1993, Cell.

[65]  J. H. Schwartz,et al.  Activation of protein kinase C by serotonin: biochemical evidence that it participates in the mechanisms underlying facilitation in Aplysia. , 1988, Journal de physiologie.

[66]  P. Andersen,et al.  Protein kinase C injection into hippocampal pyramidal cells elicits features of long term potentiation , 1987, Nature.

[67]  Y. Nishizuka,et al.  Identification of three additional members of rat protein kinase C family: delta-, epsilon- and zeta-subspecies. , 1987, FEBS letters.